The immunomodulating effects of Clarithromycin on patients with Bronchiectasis

Bronchiectasis pathogenesis has been vividly illustrated as a vicious cycle of chronic infection and inflammation with mediator release. Inflammation-driven destruction of the bronchial wall and excess of mucopurulent secretions ground for further obstruction and damage of the airway and for microbial colonization responsible for recurrent infections. Th17 cells play an important role in protection against certain extracellular pathogens, by inducing a massive tissue reaction via secretion of cytokines, chemokines, metalloproteinases and antimicrobial peptides; however, they are highly pathogenic as they may promote the development or sustenance of neutrophilic inflammation and severe autoimmunity. Indeed, the neutrophilic inflammation present in cystic fibrosis and other forms of bronchiectasis is typically associated with the increased presence of Th-17 cells. Modulation of the immunologic environment of the airways with the use of anti-inflammatory drugs in patients with chronic lung inflammatory diseases has recently been the subject of growing interest. It has been previously reported that macrolide antibiotics exhibit immunomodulating activities beyond their antimicrobial action. The macrolide Clarithromycin, in particular, has been reported to modulate pro-inflammatory cytokine expression by human neutrophils, most probably due to the downregulation of transcription factors such as NF-kB, AP-1 and specificity protein-1 and that setting is exerted via inhibition of signaling of the extracellular regulated kinase ERK- 1/2 and p38 MAPK pathway. In the view of the aforementioned data and as the effect of Clarithromycin on the Th17 response in the setting of non-CF bronchiectasis has not yet been examined, this PhD thesis had three goals: a) determination of the concentrations of IL-17 in exhaled breath condensate and in serum and of circulating levels of Th17 cells in peripheral blood in patients with non-CF bronchiectasis and assessment of any potential differences in these parameters after Clarithromycin prophylactic administration, at a dose of 500 mg daily for 12 weeks, b) assessment of potential changes in lung function parameters (FEV1 and FVC after bronchodilation, PaO2 and PaCO2) and c) assessment of quality of life changes following Clarithromycin administration for 24 weeks. Clinical data regarding sputum microbiology and number of exacerbations during study period were also recorded in parallel. For this purpose, patients with clinically stable bronchiectasis, followed on a regular basis in Outpatient Clinic of the Pulmonary Department of the University Hospital of Alexanroupolis, were studied in a prospective observational manner from February 2011 to May 2012. These patients had already been considered to receive 500 mg of Clarithromycin on a daily basis. From the initial population, 22 patients fulfilled the inclusion criteria: more than 3 infective exacerbations requiring antibiotic therapy during the previous 12 months, 24-h sputum volume> 10mL and clinically stable disease. Exclusion criteria included history of smoking, asthma and atopy, regular use of inhaled corticosteroids and respiratory tract infection or exacerbation of the disease requiring therapy with antibiotics and/or systemic corticosteroids 4 weeks prior to study. Ten healthy volunteers were also studied, in order to determine the "normal" values of the examined parameters. Samples analysis resulted in significant decreases in both, post-treatment absolute counts of CD4+IL17+ cells in peripheral blood and IL-17 levels in EBC (post-treatment CD4+IL17+ mean 2.418±0.414 cells/μl versus pre-treatment 3.202±0.507 cells/μl, p=0.036 and post-treatment IL-17 mean levels 7.16±0.47 pg/ml versus pre-treatment 9.32±0.47 pg/ml, p 10mL και σταθερή κλινική κατάσταση κατά την ένταξη στη μελέτη. Ασθενείς καπνιστές, με ιστορικό άσθματος ή ατοπίας, τακτική χρήση εισπνεόμενων κορτικοστεροειδών, λοίμωξη του αναπνευστικού ή παρόξυνση της νόσου για τις οποίες απαιτήθηκε η χρήση αντιβιοτικών και συστηματικών κορτικοστεροειδών τις προηγούμενες 4 εβδομάδες αποκλείστηκαν από τη μελέτη. Από την παρούσα μελέτη προέκυψε σημαντική μείωση των συγκεντρώσεων της IL- 17 στο εκπνεόμενο συμπύκνωμα και του αριθμού των Th17 λεμφοκυττάρων στο περιφερικό αίμα μετά από 12 εβδομάδες θεραπείας με Κλαριθρομυκίνη (7,16±0,47 pg/ml έναντι 9,32±0,47 pg/ml, p<0,001 και 2,418±0,414 κύτταρα/μl έναντι 3,202±0,507 κύτταρα/μl, p=0,036, αντίστοιχα). Η μείωση των συγκεντρώσεων της IL-17 παρατηρήθηκε τόσο στους ασθενείς που παρουσίασαν παροξύνσεις όσο και σε όσους παρέμειναν κλινικά σταθεροί κατά τη διάρκεια της μελέτης (6,72±0,37 pg/ml έναντι 9,12±0,64 pg/ml, p=0,01 και 7,69±0,9 pg/ml έναντι 9,53±0,72 pg/ml, p=0,042, αντίστοιχα). Διαπιστώθηκε, επίσης, σημαντική βελτίωση στα επίπεδα της PaO2 (77,73±2,23 mmHg έναντι 73,18±2,22 mmHg, p=0,025), ενώ αντίθετα η PaCO2, ο FEV1 και η FVC μετά από βρογχοδιαστολή παρέμειναν αμετάβλητες. Τέλος, σημειώθηκε σημαντική βελτίωση στην ποιότητα ζωής, με μείωση στις βαθμολογίες στο SGRQ, τόσο στο σύνολο (29,93±4,32 έναντι 40,14±4,4, p=0.002) όσο και στους επιμέρους τομείς του (συμπτώματα: 27,91±5,61 έναντι 38,79±4,61, p=0,036, δραστηριότητα: 38,36±5,08 έναντι 51,34±4,88, p=0,005, επιδράσεις: 25,57±4,31 έναντι 34,28±4,89, p=0,011), η οποία ήταν ανεξάρτητη της παρουσίας ή όχι μικροβιακού αποικισμού (19,38±4,73 έναντι 30,72±6,69, p=0,033 και 37,23±5,83 έναντι 46,74±5,39, p=0,029 αντίστοιχα), με το μεγαλύτερο όφελος, ωστόσω, να προκύπτει για ασθενείς αποικισμένους από P.aeruginosa (31,85±9,90 έναντι 47,07±9,47, p=0,015). Επομένως, από την παρούσα Διδακτορική Διατριβή προέκυψε ότι η μακροχρόνια προφυλακτική χορήγηση Κλαριθρομυκίνης σε χαμηλές δόσεις οδηγεί σε μείωση τόσο της τοπικής όσο και της συστηματικής Th17 φλεγμονώδους απάντησης και σε σημαντική βελτίωση της ποιότητας ζωής σε ασθενείς με βρογχεκτασίες, γεγονός ενδεικτικό μιας ευνοϊκής αντιφλεγμονώδους ή/και ανοσοτροποποιητικής επίδρασής της

Patient-Reported Outcome Measurements in Patients with COPD-Obstructive Sleep Apnea Overlap Syndrome: Time for Action?

Chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea syndrome (OSA) are common conditions that often coexist [Overlap syndrome (OS)]. OS has important implications in the diagnosis, treatment, and patient outcome of both disorders. Patient-reported outcomes (PROs) are essential to evaluate symptoms, impact of symptoms on activities of daily living, and treatment response. The present review aims to display the potential usefulness of PROs measurements (PROMs) regarding the initial evaluation and treatment of both conditions (COPD and OSA) in OS patients. More specifically, we review PROMs regarding symptoms, mental health indices and health-related quality of life in patients with OS. These PROMs have the potential to add value to clinical research and daily practice in certain aspects that are important to patients

BCG pneumonitis with a miliary radiological pattern complicating intravesical BCG immunotherapy

SUMMARY. The case is described of a 42 year-old male who presented with fever, haematuria, hypoxaemia, impaired liver function and a miliary pattern on chest X-ray while receiving intravesical BCG treatment for superficial bladder cancer. Initiation of antituberculous therapy resulted in rapid amelioration of the symptoms and the X-ray findings, and the patient left hospital in a good general state of health. Although M. bovis was not isolated from samples of sputum, bronchioalveolar lavage fluid (BALF) or bronchial biopsy tissue, the prompt response to antituberculous therapy suggests an infectious aetiology due to microbial dissemination. Pneumon 2010, 23(4):388-391

Asthma-COPD Overlap Syndrome: Recent Insights and Unanswered Questions

The term asthma-COPD overlap (ACO) has been used to identify a heterogeneous condition in which patients present with airflow limitation that is not completely reversible and clinical and inflammatory features of both asthma and chronic obstructive pulmonary disease (COPD). ACO diagnosis may be difficult in clinical practice, while controversy still exists regarding its definition, pathophysiology, and impact. Patients with ACO experience a greater disease burden compared to patients with asthma or COPD alone, but in contrast they show better response to inhaled corticosteroid treatment than other COPD phenotypes. Current management recommendations focus on defining specific and measurable treatable clinical traits, according to disease phenotypes and underlying biological mechanisms for every single patient. In this publication, we review the current knowledge on definition, pathophysiology, clinical characteristics, and management options of ACO

COVID-19 Advanced Care

The coronavirus disease 2019 (COVID-19) pandemic, related to the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused a worldwide sudden and substantial burden in public health due to an enormous increase in hospitalizations for pneumonia with the multiorgan disease. Treatment for individuals with COVID-19 includes best practices for supportive management of acute hypoxic respiratory failure. Emerging data indicate that dexamethasone therapy reduces 28-day mortality in patients requiring supplemental oxygen compared with usual care, and ongoing trials are testing the efficacy of antiviral therapies, immune modulators and anticoagulants in the prevention of disease progression and complications, while monoclonal antibodies and hyperimmune globulin may provide additional preventive strategies. Consensus suggestions can standardize care, thereby improving outcomes and facilitating future research. This review discusses current evidence regarding the pharmacotherapy of COVID-19

Prognostic Value of Serum Biomarkers in Patients with Idiopathic Pulmonary Fibrosis in Relation to Disease Progression

Background: The aim of this present study was to determine serum biomarker levels and their correlation with respiratory function and the clinical course of patients with idiopathic pulmonary fibrosis (IPF). Materials and Methods: This study included 72 IPF patients, according to the ATS/ERS criteria, in whom antifibrotic treatment was initiated. Blood samples were taken, and serum biomarkers, such as KL-6, SP-D, CCL18, CXCL13, VEGF-A, IL-8, IGFBP-1, IGFBP-2, IGFBP-7 and ICAM-1 were measured using ELISA methodology. Pulmonary function tests (FVC, TLC, DLCO-% pred) were determined at baseline and after 12 and 24 months and analyzed in correlation with the biomarkers. Results: The majority of patients (mean age 72 ± 6 years) were men (83%). The FVC and DLCO values at the 12-month follow-up were found to be statistically decreased in deceased patients (p p p = 0.021) levels were found to be increased at the 1-year follow-up in deceased patients, and similarly, the SP-D (p = 0.005) and ICAM-1 (p = 0.043) levels at the 2-year follow-up. A chi-square test revealed that 70% of the category IV GAP index was found with cut-off elevated levels of a biomarker combination (KL-6, SP-D, VEGF-A) from the ROC curve analysis (p < 0.05). Conclusion: This study provides evidence, for the first time in a Greek population, of the possibility of using a combination of KL-6, SP-D, and VEGF-A serum levels along with the GAP index

IL-26 in the Lung and Its Role in COPD Inflammation

IL-26 is a cytokine expressed by infiltrating pro-inflammatory IL-17-producing T cells in the tissues of patients with chronic lung inflammation. IL-26 induces the chemotactic response of human neutrophils to bacteria and other inflammatory stimuli. In recent years, the innovative properties of IL-26 have been described. Studies have shown that, as DNA is released from damaged cells, it binds to IL-26, which plays the role of a carrier molecule for extracellular DNA, further contributing to its binding to the site of inflammation. This mechanism of action indicates that IL-26 may serve both as a driver as well as a stimulus of the inflammatory process, leading to the installation of a noxious amplification loop and, eventually, persistent inflammation. IL-26 also demonstrates direct antimicrobial effects derived from its capability to create pores and disrupt bacterial membranes, as indicated by the presence of membrane blebs on the surface of the bacteria and cytosolic leakage pores in bacterial walls, produced in response to microbial stimuli in human airways by several different immune and structural cells. Surprisingly, while this particular cytokine induces the gathering of neutrophils in areas of infection, it also exhibits inhibitory and pro-inflammatory effects on airway epithelial and immune cells. These remarkable effects underline the necessity of a better understating of its biological behavior and its role in the pathophysiology and disease burden in several smoking-related airway inflammatory disorders, such as Chronic Obstructive Pulmonary Disease (COPD) and chronic bronchitis. In this review, we aim to discuss the current role of IL-26 in the lung, with an emphasis on systemic inflammation in patients suffering from COPD and chronic bronchitis

Eosinophilic Asthma, Phenotypes-Endotypes and Current Biomarkers of Choice

Asthma phenotyping and endotyping are constantly evolving. Currently, several biologic agents have been developed towards a personalized approach to asthma management. This review will focus on different eosinophilic phenotypes and Th2-associated endotypes with eosinophilic inflammation. Additionally, airway remodeling is analyzed as a key feature of asthmatic eosinophilic endotypes. In addition, evidence of biomarkers is examined with a predictive value to identify patients with severe, uncontrolled asthma who may benefit from new treatment options. Finally, there will be a discussion on the results from clinical trials regarding severe eosinophilic asthma and how the inhibition of the eosinophilic pathway by targeted treatments has led to the reduction of recurrent exacerbations

Cardiovascular Diseases in COPD: From Diagnosis and Prevalence to Therapy

Chronic obstructive pulmonary disease (COPD) is considered one of the leading causes of mortality. Cardiovascular comorbidities are diagnosed often in COPD patients, not only because of the common risk factors these two diseases share, but also because of the systemic inflammation which characterizes COPD and has deleterious effects in the cardiovascular system. The comorbid cardiovascular diseases in COPD result in several difficulties in the holistic treatment of these patients and affect outcomes such as morbidity and mortality. Several studies have reported that mortality from cardiovascular causes is common among COPD patients, while the risk for acute cardiovascular events increases during COPD exacerbations and remains high for a long time even after recovery. In this review, we focus on the prevalence of cardiovascular comorbidities in COPD patients, presenting the evidence regarding the interaction of the pathophysiological pathways which characterize each disease. Furthermore, we summarize information regarding the effects of cardiovascular treatment on COPD outcomes and vice versa. Finally, we present the current evidence regarding the impact of cardiovascular comorbidities on exacerbations, quality of life and survival of COPD patients